Hierarchical differentiation competence in response to retinoic acid ensures stem cell maintenance during mouse spermatogenesis.
Hierarchical differentiation competence in response to retinoic acid ensures stem cell maintenance during mouse spermatogenesis.
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DOI：
10.1242/dev.118695
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发表时间：
2015-05-01
期刊：
影响因子：
--
通讯作者：
Yoshida S
中科院分区：
文献类型：
--
作者：
Ikami K;Tokue M;Sugimoto R;Noda C;Kobayashi S;Hara K;Yoshida S
干细胞通过产生分化和自我更新的后代来确保组织的稳态。在某些组织中，这是通过确定的干细胞龛的功能来实现的。然而，在小鼠精子发生的机制是未知的，因为未分化的精原细胞（Aundiff）是能动的，并在一个'开放'的生精小管生态位环境中与分化细胞混合。Aundiff包括胶质细胞源性神经营养因子受体α1（GFRα1）+和神经生成素3（NGN 3）+亚群，这两种亚群都保留了自我更新的能力。然而，尽管GFRα1+细胞构成了稳态干细胞库，但NGN 3+细胞显示出更高的分化为KIT+精原细胞的可能性，其机制尚不清楚。在本研究中，通过结合脉冲标记细胞的命运分析和维生素A缺乏模型，我们证明，在生精上皮周期中，视黄酸（RA）可能周期性地增加小管中的浓度，仅诱导NGN 3+细胞分化。基因表达的比较显示，维甲酸受体γ（Rarg）主要在NGN 3+细胞中表达，而在GFRα1+细胞中不表达，而许多其他RA反应相关基因的表达水平在两个群体中相似。RARγ的异位表达足以诱导GFRα1+细胞直接分化为KIT+细胞，而不转变NGN 3+状态。因此，RARγ在NGN 3+细胞的分化能力中起关键作用。我们提出了一种新的机制，在一个开放的生态位环境中，未分化的细胞表现出异质性的能力，以响应无处不在的分化诱导信号的干细胞的命运选择。突出显示的文章：在小鼠曲细精管的开放环境中，未分化的干细胞池通过精原细胞中视黄酸受体-γ的差异表达来维持。
Stem cells ensure tissue homeostasis through the production of differentiating and self-renewing progeny. In some tissues, this is achieved by the function of a definitive stem cell niche. However, the mechanisms that operate in mouse spermatogenesis are unknown because undifferentiated spermatogonia (Aundiff) are motile and intermingle with differentiating cells in an ‘open’ niche environment of seminiferous tubules. Aundiff include glial cell line-derived neurotrophic factor receptor α1 (GFRα1)+ and neurogenin 3 (NGN3)+ subpopulations, both of which retain the ability to self-renew. However, whereas GFRα1+ cells comprise the homeostatic stem cell pool, NGN3+ cells show a higher probability to differentiate into KIT+ spermatogonia by as yet unknown mechanisms. In the present study, by combining fate analysis of pulse-labeled cells and a model of vitamin A deficiency, we demonstrate that retinoic acid (RA), which may periodically increase in concentration in the tubules during the seminiferous epithelial cycle, induced only NGN3+ cells to differentiate. Comparison of gene expression revealed that retinoic acid receptor γ (Rarg) was predominantly expressed in NGN3+ cells, but not in GFRα1+ cells, whereas the expression levels of many other RA response-related genes were similar in the two populations. Ectopic expression of RARγ was sufficient to induce GFRα1+ cells to directly differentiate to KIT+ cells without transiting the NGN3+ state. Therefore, RARγ plays key roles in the differentiation competence of NGN3+ cells. We propose a novel mechanism of stem cell fate selection in an open niche environment whereby undifferentiated cells show heterogeneous competence to differentiate in response to ubiquitously distributed differentiation-inducing signals. Highlighted article: In the open environment of mouse seminiferous tubules, an undifferentiated stem cell pool is maintained by the differential expression of the retinoic acid receptor-γ in spermatogonia.
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影响因子：
23.9
作者：
Hara, Kenshiro;Nakagawa, Toshinori;Enomoto, Hideki;Suzuki, Mikiko;Yamamoto, Masayuki;Simons, Benjamin D.;Yoshida, Shosei
通讯作者：
Yoshida, Shosei
影响因子：
4.1
作者：
Kane, MA;Chen, N;Napoli, JL
通讯作者：
Napoli, JL
影响因子：
64.8
作者：
BRAND, N;PETKOVICH, M;DEJEAN, A
通讯作者：
DEJEAN, A
影响因子：
5.3
作者：
GIGUERE, V;SHAGO, M;VARMUZA, S
通讯作者：
VARMUZA, S
影响因子：
4.8
作者：
Gely-Pernot, Aurore;Raverdeau, Mathilde;Mark, Manuel
通讯作者：
Mark, Manuel